Methods of treating autoimmune diseases by administering monoclonal antibodies against human IL-12

Abstract

The present invention relates to novel p75 heterodimer specific anti-human IL-12 antibodies that are characterized by a higher potency and greater efficacy in neutralizing human IL-12 bioactivity than known heterodimer specific IL-12 monoclonal antibodies. The heterodimer specific antibodies recognize one or more epitopes of the human IL-12 p75 heterodimer, but do not bind to the p40 subunit alone. The heterodimer specific IL-12 antibodies neutralize rhesus monkey IL-12 bioactivity with a potency similar to their potency for neutralizing human IL-12 bioactivity making them useful IL-12 antagonists for in vivo studies in the rhesus monkey.

What is claimed is: 
     
       1. A method for treating an autoimmune disease in an individual in need thereof, comprising administering to said individual a composition comprising a monoclonal antibody formulated in a pharmaceutically acceptable carrier, said monoclonal antibody binding to human interleukin-12 (IL-12) p75 heterodimer, said p75 heterodimer comprising a p40 subunit and a p35 subunit, wherein said monoclonal antibody:
 (a) immunologically reacts with an epitope presented by the p75 heterodimer of human IL-12; and 
 (b1) neutralizes at least 90% of the bioactivity of human IL-12 as measured in an IL-12 bioactivity assay in phytohemagglutinin (PHA)-activated human lymphoblasts by inhibiting IL-12 stimulated proliferation of PHA-activated human lymphoblasts, using an antibody concentration of 0.5 μg/ml and a human IL-12 concentration of 0.25 ng/ml; or 
 (b2) neutralizes at least 90% of the bioactivity of human IL-12 as measured in an IL-12 bioactivity assay in PHA-activated human lymphoblasts by inhibiting IL-12 stimulated IFN-γ production by PHA-activated human lymphoblasts, using an antibody concentration of 0.5 μg/ml and a human IL-12 concentration of 0.25 ng/ml. 
 
     
     
       2. The method according to  claim 1  wherein the autoimmune disease is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, autoimmune diabetes mellitus, inflammatory bowel disease, Crohn's disease, ulcerative colitis, transplantation/graft-versus-host disease, and septic shock. 
     
     
       3. The method according to  claim 1 , wherein said antibody is administered parenterally, intravenously, intramuscularly, or subcutaneously. 
     
     
       4. The method according to  claim 1 , wherein said pharmaceutically acceptable carrier is selected from the group consisting of propylene glycol, polyethylene glycol, vegetable oil, olive oil, ethyl oleate, water, saline sodium chloride solution, Ringer's dextrose, dextrose, lactated Ringer's solution, and fixed oils. 
     
     
       5. The method according to  claim 1 , wherein said pharmaceutically acceptable carrier further comprises fluid and nutrient replenishers, electrolyte replenishers, anti-microbials, anti-oxidants, chelating agents, or inert gases. 
     
     
       6. The method according to  claim 1  wherein the administration of said antibody is in dosage from about 0.1-10 mg/kg two to three times/week.